title: Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia.
abstract: BACKGROUND
  Congenital sideroblastic anemias are rare disorders with several genetic causes; they are characterized by erythroblast mitochondrial iron overload, differ greatly in severity and some occur within a syndrome. The most common cause of non-syndromic, microcytic sideroblastic anemia is a defect in the X-linked 5-aminolevulinate synthase 2 gene but this is not always present. Recently, variations in the gene for the mitochondrial carrier SLC25A38 were reported to cause a non-syndromic, severe type of autosomal-recessive sideroblastic anemia. Further evaluation of the importance of this gene was required to estimate the proportion of patients affected and to gain further insight into the range and types of variations involved.
  
  
  METHODS
  In three European diagnostic laboratories sequence analysis of SLC25A38 was performed on DNA from patients affected by congenital sideroblastic anemia of a non-syndromic nature not caused by variations in the 5-aminolevulinate synthase 2 gene.
  
  
  RESULTS
  Eleven patients whose ancestral origins spread across several continents were homozygous or compound heterozygous for ten different SLC25A38 variations causing premature termination of translation (p.Arg117X, p.Tyr109LeufsX43), predicted splicing alteration (c.625G>C; p.Asp209His) or missense substitution (p.Gln56Lys, p.Arg134Cys, p.Ile147Asn, p.Arg187Gln, p.Pro190Arg, p.Gly228Val, p.Arg278Gly). Only three of these variations have been described previously (p.Arg117X, p.Tyr109LeufsX43 and p.Asp209His). All new variants reported here are missense and affect conserved amino acids. Structure modeling suggests that these variants may influence different aspects of transport as described for mutations in other mitochondrial carrier disorders.
  
  
  CONCLUSIONS
  Mutations in the SLC25A38 gene cause severe, non-syndromic, microcytic/hypochromic sideroblastic anemia in many populations. Missense mutations are shown to be of importance as are mutations that affect protein production. Further investigation of these mutations should shed light on structure-function relationships in this protein.
authors.affiliation: AP-HP, Service de Biochimie Génétique et Hormonale, Hopital Bichat, Paris, INSERM, Centre de Recherche Biomédicale Bichat Beaujon, Université Paris Diderot, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Mayka
authors.initials: M
authors.lastname: Sanchez
authors.forename: Marion
authors.initials: M
authors.lastname: Sweeney
authors.forename: Gilles
authors.initials: G
authors.lastname: Hetet
authors.forename: Briedgeen
authors.initials: B
authors.lastname: Kerr
authors.forename: Erica
authors.initials: E
authors.lastname: Moran
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fuster Soler
authors.forename: Karim
authors.initials: K
authors.lastname: Maloum
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Caroline
authors.initials: C
authors.lastname: Oudot
authors.forename: Axelle
authors.initials: A
authors.lastname: Lascaux
authors.forename: Corinne
authors.initials: C
authors.lastname: Pondarré
authors.forename: Julian
authors.initials: J
authors.lastname: Sevilla Navarro
authors.forename: Sudharma
authors.initials: S
authors.lastname: Vidyatilake
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Alison
authors.initials: A
authors.lastname: May
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic / Q000235:genetics*; D002675:Child, Preschool; D005091:Exons; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C553226:Slc25a38 protein, human